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1.
Cancer ; 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38470379

RESUMO

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.

2.
Lancet Oncol ; 24(8): 892-902, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37429302

RESUMO

BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.


Assuntos
Sarcoma Alveolar de Partes Moles , Neoplasias de Tecidos Moles , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Critérios de Avaliação de Resposta em Tumores Sólidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , DNA Helicases , Proteínas Nucleares , Fatores de Transcrição
5.
Eur J Cancer ; 171: 183-192, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35728378

RESUMO

BACKGROUND: We retrospectively investigated the role of (neo)adjuvant chemotherapy in patients with primary, localized angiosarcoma. METHODS: We selected all patients with primary, localized angiosarcoma, who had received radical surgery between January 2005 and December 2019 at 33 European sarcoma reference centers. The primary objective was to compare the outcome of patients who received (neo)adjuvant chemotherapy versus those who did not, in terms of overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS). To reduce the risk of confounding due to imbalance, a propensity-score matching(PSM) was performed. Finally, subgroups analysis was performed according to tumor site, tumor size (< 50 mm or ≥ 50 mm) and patients predicted 10-years OS according to the nomogram sarculator (two different cutoff-values were applied: ≤ 33% or > 33% and < 60% or ≥ 60%). RESULTS: 362 patients were analyzed: 149 (41.2%; treated group) received (neo) adjuvant chemotherapy and 213 (58.6%; control group) did not. The median follow-up for the OS endpoint was 5.1 years (95% CI: 4.0-5.5). The OS-HR was 0.58 (95%CI: 0.40-0.83; p-value = 0.003) in the univariate analysis and 0.74 (95% CI: 0.38-1.43; p = 0.367) in the PSM analysis. The DFS-HR was 0.75 (95% CI: 0.57-0.98; p-value = 0.036) in the univariate analysis, and 0.91 (95% CI:0.56-1.48; p-value = 0.7) in the PSM analysis. The DMFS-HR was 0.75 (95% CI: 0.55-1.02; p-value = 0.065) in univariate analysis and 0.92 (95% CI: 0.53-1.61; p-value = 0.769) in the PSM analysis. Subgroup analysis revealed no heterogeneity of results in strata of tumor site. On the contrary, there was a trend for heterogeneity according to tumor size and patient's risk of death. For all the endpoints analyzed, patients with tumors smaller than 50 mm or at lower risk of death seem to have no benefit from chemotherapy, while patients with larger tumors or at higher risk of death at 10 years seem to derive substantial benefit. CONCLUSION: This large, retrospective study suggests that patients affected by > 50 mm and/or high-risk primary, localized angiosarcoma could benefit from (neo)adjuvant chemotherapy.


Assuntos
Hemangiossarcoma , Sarcoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Hemangiossarcoma/tratamento farmacológico , Humanos , Estudos Retrospectivos , Sarcoma/tratamento farmacológico
6.
Int J Cancer ; 151(8): 1335-1344, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35603906

RESUMO

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Estudos Retrospectivos
7.
J Oncol ; 2022: 3449660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222642

RESUMO

INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. RESULTS: ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8-23.5) and 3.5 months (95% CI, 2.8-9.7), and median overall survival was not reached (NR) (95% CI, 37.8-NR) and 24 months (95% CI, 9.9-NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (p=0.07) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (p=0.07). CONCLUSION: Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.

8.
Bull Cancer ; 108(4): 415-423, 2021 Apr.
Artigo em Francês | MEDLINE | ID: mdl-33678409

RESUMO

The management of oncology patients, especially hospitalized patients, can lead to almost daily discussions regarding therapeutic limitations. Here, we review the history and propose a summary of the texts framing the notion of "withholding and withdrawing life-sustaining treatment" in oncology practice in France. This decision is regulated by the Claeys-Léonetti Law of February 2, 2016 recommending a collegial discussion and its documentation in the medical record. The decision to withhold or withdraw life-sustaining treatments is the subject of discussion between the patient, his physicians and his family and may take place at any time during his management. The work of intensive-care physicians provides many useful recommendations for acute oncology situations, however articles specific for oncology practice are scarce; this is a topic that oncologists must take up.


Assuntos
Oncologia/legislação & jurisprudência , Neoplasias/terapia , Cuidados Paliativos , Assistência Terminal , Suspensão de Tratamento , Tomada de Decisão Clínica , Sedação Profunda/história , França , História do Século XX , História do Século XXI , Humanos , Futilidade Médica/legislação & jurisprudência , Cuidados Paliativos/história , Cuidados Paliativos/legislação & jurisprudência , Relações Médico-Paciente , Relações Profissional-Família , Assistência Terminal/história , Assistência Terminal/legislação & jurisprudência , Suspensão de Tratamento/história , Suspensão de Tratamento/legislação & jurisprudência
9.
Front Oncol ; 10: 594445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33330082

RESUMO

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

11.
Bull Cancer ; 107(3): 375-380, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31812284

RESUMO

We summarize here available data about systemic treatments of desmoids tumors, as well in adult patients as pediatric patients. Until 2018, the level of evidence associated with these treatments (NSAI, hormonal therapies, tyrosine kinase inhibitors, chemotherapy) was very low, based on retrospective studies or non-randomized phase 2 trials with limited number of cases. In 2018-2019, 2 large randomized trials have been published, including one large superiority phase 3 trial comparing sorafenib to placebo. This trial clearly demonstrates the clinical benefit of sorafenib over placebo (level of evidence IA). To conclude, wait-and-see policy must be the first-line approach, systemic treatment is indicated in case of disease progression. Randomized trials are feasible in this exceptional disease.


Assuntos
Fibromatose Agressiva/terapia , Adulto , Fatores Etários , Antineoplásicos/uso terapêutico , Criança , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Estudos Cross-Over , Humanos , Indazóis , Metotrexato/uso terapêutico , Estudo de Prova de Conceito , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe/uso terapêutico , Sulfonamidas/uso terapêutico , Vimblastina/uso terapêutico
12.
Ann Surg Oncol ; 27(5): 1693-1699, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31773519

RESUMO

BACKGROUND: Metastatic phyllodes tumors have poor prognosis with median overall survival of 11.5 months. The objective of this study is to identify prognostic factors and the best options for management of metastatic malignant phyllode tumors (MMPTs). PATIENTS AND METHODS: A multicentric retrospective study, including cases of MMPT from 10 sarcoma centers, was conducted. The primary end-point was overall survival (OS), and the secondary end-point was the clinical benefit of chemotherapy (CBCT) rate. RESULTS: 51 MMPT patients were included. Median time from diagnosis to metastatic recurrence was 13 months. Management of MMPT consisted in surgery of the metastatic disease for 16 patients (31.3%), radiation therapy of the metastatic disease for 15 patients (31.9%), and chemotherapy for 37 patients (72.5%). Median follow-up was 62.1 months [95% confidence interval (CI) 31-80 months]. Median OS was 11.5 months (95% CI 7.5-18.7 months). On multivariate analysis, two or more metastatic sites [hazard ratio (HR) 2.81, 95% CI 1.27-6.19; p = 0.01] and surgery of metastasis (HR 0.33, 95% CI 0.14-0.78; p = 0.01) were independently associated with OS. The CBCT rate was 31.4% and 16.7% for the first and second lines. Polychemotherapy was not superior to single-agent therapy. Alkylating-agent-based chemotherapy, possibly associated with anthracyclines, was associated with a better CBCT rate than anthracyclines alone (p = 0.049). CONCLUSIONS: The results of this study emphasize the impact of the number of metastatic sites on survival of MMPT patients and the leading role of metastasis surgery in MMPT management. If systemic therapy is used, it should include alkylating agents, which are associated with a better clinical benefit.


Assuntos
Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Metástase Neoplásica/terapia , Tumor Filoide/terapia , Procedimentos Cirúrgicos Operatórios , Adulto , Idoso , Idoso de 80 Anos ou mais , Alquilantes/uso terapêutico , Neoplasias da Mama/mortalidade , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Tumor Filoide/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
14.
Crit Rev Oncol Hematol ; 143: 62-66, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494310

RESUMO

We review the role of hormonal therapy in the management of different conjunctive tumors. Progestin and aromatase inhibitors seem active in low-grade endometrial stromal sarcoma, but larger case-series are needed. There is no evidence to support the use of hormonal therapy as an adjuvant treatment for low-grade endometrial stromal sarcoma. We did not find relevant data on the use of hormonal therapy for other uterine sarcomas (e.g., high-grade endometrial sarcoma, undifferentiated uterine sarcoma, and adenosarcoma). Gonadotropin-releasing hormone agonist, anti-estrogens and aromatase inhibitor seem active in advanced aggressive angiomyxoma, but larger studies are warranted. The use of aromatase inhibitor in estrogen-receptor-positive uterine leiomyosarcoma requires further clinical investigation. There is no evidence supporting the use of hormonal therapy in desmoid-type fibromatosis. International collaboration efforts are warranted to better explore the role of hormonal therapies in management of estrogen-receptor-positive uterine leiomyosarcoma, low-grade endometrial stromal sarcoma, and aggressive angiomyxoma.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Inibidores da Aromatase/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Feminino , Fibromatose Agressiva/tratamento farmacológico , Fibromatose Agressiva/patologia , Humanos , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/patologia , Sarcoma/patologia , Sarcoma do Estroma Endometrial/patologia , Neoplasias Uterinas/patologia
15.
Anticancer Res ; 39(6): 2993-3002, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177140

RESUMO

AIM: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. PATIENTS AND METHODS: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. RESULTS: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. CONCLUSION: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
16.
BMC Cancer ; 18(1): 963, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305054

RESUMO

BACKGROUND: We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. METHODS: Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. RESULTS: Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. CONCLUSIONS: De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. TRIAL REGISTRATION: Retrospectively registered on EudraCT N° 2009-017020-59 and NCT01303497 (February 24, 2011).


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Bevacizumab/administração & dosagem , Biomarcadores Tumorais , Hemangiossarcoma/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Feminino , Hemangiossarcoma/sangue , Hemangiossarcoma/fisiopatologia , Humanos , Pessoa de Meia-Idade , Fator de Crescimento Placentário/sangue , Prognóstico , Fator A de Crescimento do Endotélio Vascular/sangue
17.
Eur J Cancer ; 99: 28-36, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29902612

RESUMO

INTRODUCTION: The placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over. METHODS: From June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm. RESULTS: PFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35-0.71; p < .0001). OS was not statistically significant different (HR = 0.78; 0.54-1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45-71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84-1.73; p = .30) without impact on OS. CONCLUSIONS: Observed PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Progressão da Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Placebos , Intervalo Livre de Progressão , Sarcoma/mortalidade , Adulto Jovem
18.
JAMA Oncol ; 4(1): 93-97, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28662235

RESUMO

IMPORTANCE: There is a strong rationale for treating sarcomas with immunotherapy. OBJECTIVE: To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. INTERVENTION OR EXPOSURE: Pembrolizumab in combination with metronomic cyclophosphamide. MAIN OUTCOMES AND MEASURES: There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. RESULTS: Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1-positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. CONCLUSIONS AND RELEVANCE: We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02406781.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Ciclofosfamida/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Macrófagos/fisiologia , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/imunologia , Sarcoma/tratamento farmacológico , Administração Metronômica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/imunologia , Movimento Celular/imunologia , Ciclofosfamida/efeitos adversos , Ativação Enzimática , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/imunologia , Humanos , Macrófagos/patologia , Masculino , Redes e Vias Metabólicas/imunologia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma/imunologia , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/imunologia , Adulto Jovem
19.
Sci Rep ; 7(1): 17917, 2017 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29263409

RESUMO

Ewing's sarcoma family of tumors (EFTs) is a group of rare and aggressive tumors. Data on EFTs in patients (pts) ≥ 50 years are limited and these pts are often not eligible for clinical trials. Some, but not all, studies have reported inferior outcome for older pts with EFTs. We conducted an IRB-approved retrospective analysis among centers of the French Sarcoma Group on pts diagnosed with EFTs at age ≥50 between 2000 and 2012. Clinical features, treatment modality and outcomes were analyzed. Seventy-seven pts were identified, including 36 females (46.8%) and the median age at diagnosis was 56 years (range: 50-86). The primary tumor was located in soft tissue in 59 pts (76.6%). Fifty-six pts (72.7%) had localized disease, among them 49 (87.5%) received chemotherapy in addition to local therapy. Their estimated 3-yr OS and event-free survival (EFS) rates were respectively 73.3% and 62.2%. Recurrence occurred in 43 pts. The estimated 3-yr OS rate was 37% in pts with metastatic disease at presentation. EFTs in pts ≥50 years are more likely to originate from soft tissue and their outcomes appear to be worse than that of younger pts treated with modern protocols.


Assuntos
Neoplasias Ósseas/mortalidade , Neoplasias Pulmonares/mortalidade , Recidiva Local de Neoplasia/mortalidade , Sarcoma de Ewing/mortalidade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Radioterapia/métodos , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Procedimentos Cirúrgicos Operatórios/métodos , Taxa de Sobrevida , Resultado do Tratamento
20.
Eur J Cancer ; 83: 125-131, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28735069

RESUMO

PURPOSE: The outcome of desmoid-type fibromatosis (DTF) is unpredictable. Currently, a wait-and-see approach tends to replace large en bloc resection as the first therapeutic approach. Nevertheless, there are no validated factors to guide the treatment choice. METHOD: We conducted a prospective study of 771 confirmed cases of DTF. We analysed event-free survival (EFS) based on the occurrence of relapse after surgery, progressive disease during the wait-and-see approach, or change in therapeutic strategy. Identification of prognostic factors was performed using classical methods (log-rank test and Cox model). RESULTS: Overall, the 2-year EFS was 56%; this value did not differ between patients undergoing an operation and those managed by the wait-and-see approach (53% versus 58%, p = 0.415). In univariate analysis, two prognostic factors significantly influenced the outcome: the nature of diagnostic sampling (p = 0.466) and primary location (p = 0.0001). The 2-year EFS was only 32% after open biopsy. The 2-year EFS was 66% for favourable locations (abdominal wall, intra-abdominal, breast, digestive viscera and lower limb) and 41% for unfavourable locations. Among patients with favourable locations, the 2-year EFS was similar in patients treated by both surgery (70%) and the wait-and-see approach (63%; p = 0.413). Among patients with unfavourable locations, the 2-year EFS was significantly enhanced in patients initially managed with the wait-and-see approach (52%) compared with those who underwent initial surgery (25%; p = 0.001). CONCLUSION: The location of DTF is a major prognostic factor for EFS. If these findings are confirmed by independent analysis, personalised management of DTF must consider this easily obtained parameter.


Assuntos
Fibromatose Agressiva/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Fibromatose Agressiva/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Prospectivos , Conduta Expectante , Adulto Jovem
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